Abstract:
:Intestinal fibrosis leading to strictures remains a significant clinical problem in inflammatory bowel diseases (IBD). The role of bacterial components in activating intestinal mesenchymal cells and driving fibrogenesis is largely unexplored. Tamoxifen-inducible α-SMA promoter Cre mice crossed with floxed MyD88 mice were subjected to chronic dextran sodium sulfate colitis. MyD88 was deleted prior to or after induction of colitis. Human intestinal myofibroblasts (HIMF) were exposed to various bacterial components and assessed for fibronectin (FN) and collagen I (Col1) production. RNA sequencing was performed. Post-transcriptional regulation was assessed by polysome profiling assay. Selective deletion of MyD88 in α-SMA-positive cells prior to, but not after induction of, experimental colitis decreased the degree of intestinal fibrosis. HIMF selectively responded to flagellin with enhanced FN or Col1 protein production in a MyD88-dependent manner. RNA sequencing suggested minimal transcriptional changes induced by flagellin in HIMF. Polysome profiling revealed higher proportions of FN and Col1 mRNA in the actively translated fractions of flagellin exposed HIMF, which was mediated by eIF2 alpha and 4EBP1. In conclusion, selectivity of flagellin-induced ECM secretion in HIMF is post-transcriptionally regulated. The results may represent a novel and targetable link between the gut microbiota and intestinal fibrogenesis.
journal_name
Mucosal Immunoljournal_title
Mucosal immunologyauthors
Zhao S,Dejanovic D,Yao P,Bhilocha S,Sadler T,Schirbel A,West G,Doyon G,Lopez R,Mao R,Kurada S,El Ouali S,Grassl G,Fox PL,Cruise M,Worthley DL,de la Motte C,Fiocchi C,Rieder Fdoi
10.1038/s41385-020-0259-9subject
Has Abstractpub_date
2020-07-01 00:00:00pages
665-678issue
4eissn
1933-0219issn
1935-3456pii
10.1038/s41385-020-0259-9journal_volume
13pub_type
杂志文章abstract::Our studies have focused on understanding the mechanisms of interactions between the indigenous intestinal flora and the mammalian host in both physiological and nonphysiological conditions. In particular, we have focused on the function of innate microbial pattern recognition by Toll-like receptors in the context of ...
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